Reduce the almost epidemic increase in the occurrence of AF in the aging U.S. population. This is a critical need for which basic science and clinical tools presently exist to address and resolve into a means to reduce the clinical consequences of AF.

Feasibility and challenges of addressing this CQ or CC:

To accomplish this goal the following approaches could be taken:

GENETIC: Investigate genetic factors that drive susceptibility to atrial fibrillation in various disease states and “lone” AF.

BASIC: Investigate the principles underlying electrical and structural remodeling which facilitate and perpetuate atrial fibrillation. Use a systems approach to aid the understanding of the role of neurohormonal and other organ system influences on human cardiac electromechanical activity. Develop new imaging modalities to better characterize conduction abnormalities in three dimensions. Investigate the nature of chamber-specific channels as potential targets for AF therapies. Encourage the development of new thrombin inhibitors and other potent but safe anticoagulants.

TRANSLATIONAL: Investigate promising pharmacologic or other interventions designed to reduce the incidence of atrial fibrillation in animal models with spontaneously occurring atrial fibrillation. Create the infrastructure for a “dynamic repository” of clinically obtained fresh human cardiac tissue for the study of AF.

CLINICAL: Improve the collection of atrial fibrillation as an endpoint in large phenotyped cohorts. Evaluate the safety and efficacy of ablative procedures relative to appropriate pharmacologic therapies. Evaluate interventions which may prevent first development and recurrence of AF (statins, ACE-I/ARB, beta blockers). Investigate the use of new antiplatelet thienopyridines for stroke prevention in AF.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

Voting

We need to improve the understanding of the molecular and physiological bases of paracrine signaling of heart, and use the knowledge gained to develop improved, effective approaches to diagnose, treat, and prevent cardiac disorders.

Although myocytes comprise approximately three-fourths of the entire volume of mammalian ventricles, they account for only about one-third of all myocardial cells. Ninety percent of the remaining myocardial cells are cardiac fibroblasts which are located primarily in the interstitium. Understanding how complex paracrine signals interact at the molecular, cellular, and organ levels continues to be a challenge to investigators. Clearly, the cardiac fibroblast plays an important role in signaling by its ability to respond to a wide variety of chemical signals that are involved in the paracrine regulation of cardiac function. These and other cardiac paracrine signaling pathways need to be better elucidated before specific clinical interventions targeting them are developed.

Feasibility and challenges of addressing this CQ or CC:

This is presently an understudied area of research. Studies however suggest that paracrine factors released from fibroblasts are likely to play an important role in modulation of heart growth and function. This may be especially so in regulation of STEM cell differentiation and following insults to the adult heart.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

Voting

1) Refinement of COPD subphenotypes for therapeutics, diagnostics and mechanistic interrogation. The NIH should encourage a strong focus on a) rigorous, mechanistically-reinforced definitions (chronic bronchitis, emphysema (with and without obstruction), frequent exacerbators, combined pulmonary fibrosis and emphysema) and 2) the development and optimization of animal model systems that replicate the different subphenotypes.
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If we could develop less costly and time consuming cell and animal models of COPD that reflect meaningful subphenotypes, we would be able to not only probe basic mechanism but also have reliable test platforms for candidate therapies.

There is typically a major obstacle between the acquisition of big data from observational disease cohorts, often broad but superficial, and the translation of these findings to basic discovery efforts. The clinical researchers speak a different language than the basic investigators and traversing this chasm with grant enticements might prove helpful.

Feasibility and challenges of addressing this CQ or CC:

This would require some suspension of the classic mechanistic, hypothesis driven proposals to develop these research tools.

There would need to be some reconstruction of study sections to permit these combined clinical-basic grants. The translational PPG was in keeping with this but should be reinforced with smaller grant programs such as RO1 level grants.

Name of idea submitter and other team members who worked on this idea:
lungmatbio1

Voting

The current generation of heart,lung, and blood investigators are not equipped with competitive training needed to approach, design, and test appropriately small molecule therapeutics that may move through the FDA pipeline. Appropriate in silico ligan or structure based design, HTS, design of Pd/Pk models, "go-no-go" branchpoints in drug development, screening approaches, and drug target validation are issues that are
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The incorporation of workshops, traditional funding mechanisms (T32, F32 etc) earmarked for this type of training will help position and equip NHLBI investigators to more effectively navigate through the landscape of drug discovery and development.

Name of idea submitter and other team members who worked on this idea:
Rama Mallampalli, MD

Voting

Congressional eagerness to see research funding translate into improvements in health care may make studies that address “how-to-deliver-care-questions” seem attractive. But the answers to “how–questions” are often so context dependent that the findings are neither generalizable nor durable. The answers to “how–questions” too often become obsolete when the health-care system, the electronic medical record, or the insurance
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To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.